Manufacture of aminoalkylidene succinic acid derivatives



Patented Sept. 4, 1945 UNITED STATES iATENT OFFICE MANUFACTURE OFAMINOALKYLIDENE succmrc ACID DERIVATIVES Franz' Bergel and Aaron Cohen,Welwyn Garden City, England, assignors to Roche Products Limited, WelwynGarden City, Hertfordshire,

. England No Drawing. Application August 19, 1942, Serial No. 455,383.In Great Britain August 20, 1941 i 7 Claims.

This invention describes the synthesis of N- substitutedamino-alkylidene succinic acid derivatives, which consists in reactingaminoesters of the general Formula I with a derivative of amonoacylsuccinic acid of the Formula II.

R COOAlkyl x a COOAlkyl Y III I II

' In Formula I, R and R, which are not necessarily identical, arehydrogen, alkyl, aryl, or

jla lkyl groups or such other groups as can be attached to the a-carbonatom of a-amino acids. R" is hydrogen or an alkyl, aryl or aralkylgroup. In Formula II, X and Y which may be identical or different areCOO-alkyl or nitrile groups,

and R' is hydrogen, or an alkyl, aryl or aralkyl group. Thusformylsuccinic ester is represented by II where X=Y=COOC2H5, andR"=hydrogen.

The above reaction may be effected by mixing the reactants with orwithout external heating, whereby a molecular proportion of water iseliminated with the formation of the reaction product which isrepresented by the Formula III.

In some cases where the free acyl succinic acid derivative is moreconveniently handled in the form of its alkali metal derivativepreferably its potassium derivative, the reaction is carried out withthe hydrochloride of the amino-acid ester.

Y R=CH3,

The following examples, in which the partsgare by weight, serve toillustrate how the invention may be carried into eii'ect:

Example 1 8.1 parts of diethyl-a-formylsuccinate. are

the constitution expressed by Formula III where R'=R"=R"'=H,alkyl=C=I-Iz, and X=Y=COOC2H5.

Example 2 g Example 3 10.1 parts of diethyl a-fOllIlYlSllCClllEtG aremixed with 5.5 parts, or slightly more than the equivalent amount, ofthe ethyl ester of glycine. The product is isolated as described aboveand has a'boiling point of about 175-C./0.6 mm. It has the Formula III,in which A mixtur of 10.8 parts of diethyl-a-acetylsuccinate and 5.5parts of the ethyl ester of glycine is heated on the water-bath for 2hours. Some water separates and this is removed by distiliing withbenzene. From the cooled mixture a small amount of diketopiperazineseparates andv this is removed by filtration. The resulting oil isfractionated under reduced pressure and after a mixed with 4.7 parts ofthe ethyl ester of a 'ala nine. The mixture immediately becomes warm andsoon turns turbid with th separation of water. After the mixture hasbeen kept at room temperature for about an hour,. some benzene is addedand the water is removed by distilling oil .the benzene, finally underreduced pressure.

Alternatively, the water may be removed in the first Place in. theprocess 'of submitting the reaction mixture to vacuum distillation whichyields the product as a clear pale yellow oil of boiling pointapproximately 155 C./0.05 mm. This is obtained in almost quantitativeyield and has foreri1nof a small amount of unchanged diethyI-aacetylsuccinate, the product-is obtainedas a pal yellow liquid boilingat approximately 185 C. at 0.6 mm. This has the Formula III in whichR=R=R"H, alkyl=CzH5, R"'=CH3 and X=Y=COOC2H5.

Erample' 5 5.65 partsfof diethyl 'a-formylsuccinate are mixed with.3.7parts of the ethyl ester of sarcosine. The hot mixture is treated as inExample 1 to isolate the product which is obtained in about yield as ayellow liquid of boiling point 170 C./0.1 mm. This has the-Formula IIIin and X=Y=COOG2H5.

Example 6 parts of diethyl a-formylsuccinate are mixed with 3 parts ormethyl a-aminoisobutyrate. The mixture becomes warm and is treated as inExample l for the isolation of the product which has a boiling pointof-about 155-160 C./0.1 mm. It has the Formula III in which R=R'=CH:,R"=R"'=H, alkyl=CHa and X=Y=COOC2H5.

Example 7 X=Y=COOC2H5 Emmple 8 13 parts of diethyl u-formylsuccinate aremixed with an equal weight of the ethyl ester 0? N- benzyl alanine(ethyl or benzylaminopropionate). The mixture becomes warm and is heatedon the water bath for 2 hours. Water is removed by adding benzene anddistilling off the latter. The residual oil is dried in vacuo andtreated with anhydrous ether to precipitate a small amount of thediketopiperazine derivative corresponding to N-benzylalanine. This isilltered off, the ether removed by evaporation and the residual oilheated to about 150 C. at a pressure of less than 1 mm. to remove anyunchanged diethyl a-formylsuccinate. The residual oil, about 22 parts,is substantially the required Product III in which R=CH3, R'=R"==H,

R"=CH2CsHs alkyl=C2H and X=Y=COOC2H5.

Example 9 4 parts of ethyl-a-formyl-p-cyanopropicnate (prepared by thecondensation of ethyl formate with ethyl-fi-cyanopropionate in thepresence of sodium or potassium in a similar manner to the preparationof the known ethyl-a-formylsuccinate, boiling point=135 C. at 10 mm.)are mixed with 3.4 parts of the ethyl ester of 02-818.- nine. Themixture becomes warm immediately and after standing at room temperaturefor a few hours is submitted to a vacuum distillation. The productobtained is an almost colourless oil having a boiling point ofapproximately 160 C.

at 0.02 mm, It has the Formula III, in which R=CHa R'=R"=R"'=H,alkyl=CzH5, X=CN, and Y==COOC2H5. (Found: C=56.8; H=='7.3; C12H1aO4N2requires C=56.7, H=7.1%.)

Example 10 The hydrochloride of the ethyl ester of glycine was mixed ina dry state with somewhat less than the equivalent amount of thepotassium salt of formylsuccinonitrile. (This compound is prepared bythe condensation of equivalent amounts of ethyl formate andsuccinonitrile in the pres-' move the water which separates.

removal of the solvent the residue is warmed under reduced pressure toremove any .unchanged glycine ester. The product is then obtained as aviscous oil and consists of the Compound III, in which R:R'=R"=R"=H,alkyl=CzH5,

X=Y=CN Example 11 17.5 parts of dimethyl a-formylsuccinate are mixedwith 19.5 parts of the methyl ester of N- benzylalanine (methyla-bBIlZYl-flllllllOPIOPIlO- nate). The mixture becomes warmspontaneously and is heated on the water-bath for 1 hour, preferablywith the occasional addition of some benzene and application of reducedpressure to re- After cooling for several hours, the mixtur is treatedwith ether to. precipitate a small amount of diketopiperaz'inederivative (corresponding to N-benzylalanine) which is filtered off. Theethereal solution is washed with sodium bicarbonate solution, dried,evaporated and the residue distilled in a vacuum yielding, in goodquantity, the prod-. uct as a yellow oil of boiling point approximately195 C./O.3 mm. It has the Formula III, in which R=CH3, R' R"'=H,R"=CH2C6H5, alkyl=CHa and X=Y=CO'OCH3.

Example 12 9.5 parts of methyl a-formyl-p-cyanopropionate (which has aboiling point of approximately 130 C./l0 mm. and is prepared similarlyto the ethyl ester used in Example 9, by the condensation of ethylformate with methyl p-cyanopropionate in the presence of sodium,potassium, or their alcoholates) are mixed with 13 parts of the methylester of N-benzylalanine. The mixture becomes warm and is worked up asdescribed in Example 11. The product distils at about 205 C./0.4 mm. asa golden yellow oil. It has the Formula 111, in which R=CH3, R'=R'=H,

The methyl ester of N-benzylalanine used as starting material inExamples 11 and 12 is prepared as follows. Equimolecular amounts ofbenzaldehyde and alanine methyl ester are mated. The mixture becomeswarm and is kept at 45-50v C. for about 45 minutes. The cloudy mixtureis treated during this period with portions of anhydrous sodium sulphateto remove water formed -It is then decanted and the sodium sulphateExample 13 The dry potassium salt of formylsuccinonitrile is mixed witha slight excess over'the molecular equivalent of the hydrochloride ofmethyl a-benzylaminopropionate, and the mixture is treated on a boilingwater bath under reduced pressure for2 hours. It is then cooled andshaken with ether and water. The ethereal extract is washed with sodiumbicarbonate solution, water, and dried. After removal of the ether, theresidue is distilled in a good vacuum yielding the product as a goldenyellow oil of boiling point about 1'15- 180 C./0.005 mm. It has theFormula III, where R=CH3, R'=R"'=H, R"=CH2.CH5, X=Y=CN and alkyl=CHa.

We claim:

1. A process for the manufacture of an N-substituted aminoalkylidenesuccinic acid compound selected from the group consisting of esters andnitriles oi the general formula:

which comprises reacting an amino ester of the general formula:

R COOAlkyl R/I%IH RI! with a monoacylsuccinic acid compound selectedfrom the group consisting of esters and nitriles of the general formula:

which comprises reacting by heating an amino ester of the generalformula:

R\(|3OOAlkyl R NH with a monoacylsuccinic acid compound selected fromthe group consisting of esters and nitriles of the general formula:

RIII I where R, R and R' are selected from the group consisting ofhydrogen and alkyl, and R" is selected from the group consisting ofhydrogen, alkyl and aralkyl radicals, X is selected from the groupconsisting of C0O-alkyl and nitrile radicals, and Y is selected fromthe, group consisting of COO-alkyl and nitrile radicalsf-r 3. As newchemical substances, an N-substituted amino-alkylidene succinic acidcompound selected from the group consisting of esters and nitriles ofthe general formula:

1 $112 R C O OAlkyl C-Y I ll where R, R and R are selected from thegroup consisting of hydrogen and alkyl, R" is selected from the groupconsisting of hydrogen, alkyl, and aralkyl radicals, X is selected fromthe group consisting of COO-alkyl and nitrile radicals, and Y isselected from the group consisting of C00- alkyl and nitrile radicals.

4. As a new chemical substance an N-substituted amino-alkylidenesuccinic acid ester having the formula:

5. As a new chemical substance an N-substituted amino-alkylidenesuccinic acid ester having the formula:

COOCH:

H: COOCH: -COOCH;

6. As a new chemical substance an N-substituted amino-alkylidenesuccinic acid nitrile having the formula:

7. A process for the manufacture of an N substituted amino-alkylidenesuccinic acid compound selected from the group consisting of esters andnitriles ;.of the general formula:

which comprises reacting the hydrochloride of i an amino ester of thegeneral formula:

R C'O-OA-lkyl \l R/ \NH I l/I with an alkali metal compound of amonoacyl- 0 RIII where R, R and R' are selected from the groupconsisting of hydrogen and alkyl, R" is selected from the groupconsisting of hydrogen, alkyl, and aralkyl radicals, X is selected fromthe group consisting of COOAlkyl and nitrile radicals, and

- Y is selected from the group consisting of CO0- Alkyl and nitrileradicals.

FRANZ BERGEL. AARON COHEN.

